Foot amputation is costly and prevalent, especially in older adults with diabetes, neuropathy, and vascular disease. The pathway to amputation includes fracture, structural deformities, ischemic vasculopathy and ulceration. Late recognition of bony complications delays interventions that could prevent amputation. This proposal is significant as it will identify image-based indices of pedal bone quality and quantity that are eary prognosticators of foot amputation in high-risk populations. The objective of this grant application is to test image-based measures of pedal bone quality and quantity as predictors of fracture strength in human 2nd metatarsals and 2nd cuneiforms. In Aim 1 the PIs will test image-based indices of pedal bone strength using mechanical testing. In Aim 2 they will compare volumetric quantitative computed tomography (vQCT) image-based measures to the reference standard of microCT. The PIs propose a novel study of image-based pedal bone quality and quantity measures from amputated and cadaver feet of advanced age with diabetes. They will perform multiple regression analysis using microCT-derived bone quality and quantity indices to predict whole-bone monotonic ultimate fracture force. The expectation is that the best model to predict bone fracture will include one or more bone quality indices. To test the clinical relevance of these measures the PIs compare microCT measures to similar vQCT-derived measures obtained prior to bone excision. This application will continue successful collaborations of a multi-professional team of clinical, image, engineering scientists and surgeons who have focused their expertise on developing and assessing image-based biomarkers to improve the recognition of neuropathy- and vasculopathy-induced bony complications of the foot that lead to amputation. PUBLIC HEALTH RELEVANCE: This application aims to assess novel candidate image-based biomarkers of pedal bone quality obtained from high resolution microCT and clinical vQCT scans. The PIs aim to determine the extent each biomarker predicts ultimate monotonic loading to fracture/failure (the reference standard for bone strength) in excised human tarsal and metatarsal bones from amputated and cadaver feet. Image-based biomarkers of pedal bone quality will be used to predict risk for lower extremity amputation in individuals with neuropathy and vascular diseases.